CN109195588B - Use of aminosugars as plasticizers - Google Patents

Use of aminosugars as plasticizers Download PDF

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CN109195588B
CN109195588B CN201780028400.5A CN201780028400A CN109195588B CN 109195588 B CN109195588 B CN 109195588B CN 201780028400 A CN201780028400 A CN 201780028400A CN 109195588 B CN109195588 B CN 109195588B
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meglumine
polyvinyl alcohol
melt extrusion
pva
composition
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CN109195588A (en
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D·卢巴达
郑梦遥
A·埃利亚
N·迪加洛
A-N·努特尔
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Merck Patent GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/022—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor characterised by the choice of material
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/0016—Plasticisers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/005—Stabilisers against oxidation, heat, light, ozone
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/16—Nitrogen-containing compounds
    • C08K5/17—Amines; Quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L29/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers
    • C08L29/02—Homopolymers or copolymers of unsaturated alcohols
    • C08L29/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2029/00—Use of polyvinylalcohols, polyvinylethers, polyvinylaldehydes, polyvinylketones or polyvinylketals or derivatives thereof as moulding material
    • B29K2029/04—PVOH, i.e. polyvinyl alcohol
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2329/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Derivatives of such polymer
    • C08J2329/02—Homopolymers or copolymers of unsaturated alcohols
    • C08J2329/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids

Abstract

The invention relates to the use of aminosugars as plasticizers in formulations comprising polymers as carriers for active ingredients, in particular compositions which are intensively mixed by processing in melt extrusion and subsequently formulated by suitable aftertreatment.

Description

Use of aminosugars as plasticizers
The invention relates to the use of aminosugars as plasticizers in formulations comprising polymers as active ingredients, in particular as carriers for compositions which are intensively mixed by processing in melt extrusion and subsequently formulated by suitable post-processing.
Background
Currently, the improvement of drug solubility and dissolution is an important issue, especially for Biopharmaceutical Classification System (BCS) class II compounds. Various methods have been used to enhance the solubility and dissolution of poorly water soluble drugs, such as Solid Dispersion (SD), salt formation, solubilization, and particle size reduction. Thus, solid dispersions can be produced by a number of methods including, but not limited to, spray drying, melt extrusion, and thermodynamic compounding.
The SD method is one of the most commonly used pharmaceutical methods for enhancing the oral bioavailability of drugs with low aqueous solubility. Conventional methods using organic solvents have been widely studied, but have a potential problem of residual organic solvents.
Over the last two decades, Hot Melt Extrusion (HME) technology has been developed to produce SD. HME is one of the most widely used processing techniques in the plastics industry. Based on the knowledge of the plastics industry, formulators can extrude combinations of drugs, polymers, and plasticizers into various final forms to achieve a desired drug release profile. HME has some significant advantages over other traditional methods. For example, it is solvent-free, involves a continuous drying process, and requires fewer process steps, provides continuous handling and scale-up capability, provides better content uniformity and can greatly improve bioavailability due to higher degree of dispersion.
The active ingredient is mixed with the other ingredients in a dry state. The hot melt extrusion mixture of active ingredient, thermoplastic excipient and other functional processing aids is filled in a hopper or feeder and delivered, mixed, heated and softened or melted within an extruder.
The extrusion process subjects the material to a heating process under intensive mixing and the material is extruded through a nozzle to obtain an extrudate which can be milled or micronized to obtain granules or particles which are then incorporated into a suitable dosage form. Twin screw extruders are one of the most popular and have advantages such as short transit times, convenient material feeding, high shear kneading and less overheating.
During this extrusion process, the thermoplastic carrier may be mixed with the pharmaceutically active substance and optionally inert excipients and further additives. The mixture is fed into a rotating screw which conveys the powder to a heating zone where shear forces are applied to the mixture until a molten mass is obtained.
For amorphous dispersions by melt extrusion, the polymer carrier must first have a thermoplastic that allows the polymer to pass through the extruder, on the other hand, the carrier must be thermally stable at barrel temperatures above the glass transition temperature or melting point of the polymer.
As mentioned above, in a hot melt extrusion process, the active ingredient is mixed with and embedded in excipients, such as polymers, and plasticizers. In addition, the drug substance is exposed to elevated temperatures for a period of time. Although there are a number of factors that affect the residence time distribution of the extruded material, these times are typically in the range of 1 to 2 minutes (Breitenbach J., Melt extrusion: from process to drug delivery technology Eur. J. Pharm Biopharm. (2002),54, 107- "117).
Prolonged exposure to high temperatures can lead to decomposition of thermally labile compounds or accelerate decomposition of chemically labile compounds. However, the addition of processing aids such as plasticizers can allow processing to be carried out at lower temperatures (Schilling S.U. et al; Citric acid as a solid-state plastizer for Eudragit RS PO; J.Pharm. Pharmacol., (2007),59(11), 1493-.
Thus, as a carrier for applying (hot) melt extrusion, the polymer should have suitable properties, such as: thermoplastic, suitable glass transition or melting points, thermal stability at the desired processing temperature, unexpected chemical interaction with the active ingredient, and the like.
In this case, polyvinyl alcohol (PVA) is an excellent compound suitable for melt extrusion as a carrier (hot melt) for pharmaceutically active ingredients.
Polyvinyl alcohol (PVA) is a synthetic water-soluble polymer with excellent film-forming, adhesive and emulsifying properties. It is prepared from polyvinyl acetate, wherein the functional acetate groups of the resulting esterified polymer are partially or completely hydrolyzed to form functional alcohol groups.
The chemical and physical properties of PVA, such as viscosity, solubility, thermal properties, etc., depend to a large extent on its degree of polymerization (chain length of the PVA polymer) and hydrolysis.
As the degree of hydrolysis increases, the solubility of the polymer in aqueous media increases, but the crystallinity of the polymer also increases. In addition to this, the glass transition temperature varies depending on the degree of hydrolysis thereof. For example, 38% of the hydrolyzed material has no melting point, but has a glass transition temperature of about 48 deg.C, while 75% -88% of the hydrolyzed material has a melting temperature of about 190-200 deg.C.
Polyvinyl alcohol is soluble in water, but is practically insoluble in almost all organic solvents, except in some cases, such as ethanol. This aspect of the polymer makes it difficult to form amorphous and solid dispersions by spray drying when the drug also has limited solubility in aqueous media.
US 5,456,923A provides a process for preparing solid dispersions which overcomes the disadvantages of conventional production techniques for solid dispersions. The method comprises the use of a twin screw extruder in the preparation of the solid dispersion. Accordingly, a solid dispersion can be conveniently prepared without heating the drug and the polymer up to or beyond their melting points and without using an organic solvent to dissolve both components, and the resulting solid dispersion has excellent performance characteristics. The process claims a natural or synthetic polymer and can be used as a feedstock, wherein the function of the polymer is not adversely affected by passage through a twin-screw extruder.
EP 2105130 a1 describes a pharmaceutical formulation comprising a solid dispersion with an active substance in amorphous form embedded in a polymer and an external polymer which acts as a recrystallization inhibitor separate from the solid dispersion. An external polymer is claimed as a solution stabilizer. The active substance should be slightly soluble or sparingly soluble in water. Thermoplastic polymers are claimed as drug carriers to form solid dispersions. The solid dispersion is claimed to be obtained by melt extrusion. The process comprises melting and mixing the polymer and active ingredient, cooling, grinding, mixing with an external polymer, and preparing the pharmaceutical formulation. Melting is claimed to be carried out at a temperature below the melting point of the drug. Also claimed is a T melting above the polymer g Or melting point, but 0.1-5 ℃ below the melting point of the API. Pharmaceutical grade PVA typically has a melting point above 178 ℃ but a glass transition temperatureThe degree is in the range of 40-45 ℃.
Thus, polyvinyl alcohol (PVA) can be applied in various routes of administration to treat various medical conditions, and it is used in a variety of pharmaceutical dosage forms, including ophthalmic, transdermal, topical and, in particular, oral applications.
However, in order to prepare a specific dosage formulation of an active ingredient in the form of a solid dispersion in a polymer matrix consisting of PVA, the active ingredient should be embedded and homogeneously distributed in the polymer matrix. It is desirable to achieve this by hot melt extrusion.
The requirements for a thermoplastic polymer that can be used as an HME excipient are: pharmaceutical grade, suitable glass transition temperature, high thermal stability, non-toxicity and high biocompatibility. Since PVA has been found to fulfill essential requirements in this respect, PVA may be selected as a carrier for the contained active compound under certain conditions in pharmaceutical formulations. At present, PVA is a well-known polymer with varying degrees of hydroxylation melting point, but is too high for hot-melt extrusion processes with active ingredients.
Problems to be solved
For the preparation of pharmaceutical formulations in the form of solid dispersions, it is common practice to homogenize the desired ingredients with one another by hot-melt extrusion. However, due to the above-mentioned problematic chemical and physical properties of polyvinyl alcohol (PVA) already present, it is difficult to prepare corresponding solid compositions comprising PVA as carrier for the active ingredient by hot-melt extrusion without affecting the decomposition of the active ingredient and optionally parts thereof at the desired temperature.
It is therefore an object of the present invention to provide suitable additives by means of which the melting point of the entire mixture with the pharmaceutically active ingredient and PVA as carrier can be lowered to a temperature below the melting point T of the applied PVA m And as low as the temperature at which the active ingredient remains stable during melt extrusion. It is another object of the present invention to provide suitable additives by means of which the viscosity of a mixture comprising PVA or excipients as a carrier for the active ingredient during extrusion is adjusted. It is another object of the present invention to provide additivesAdditives, by means of which the viscosity of the mixture is adjusted in a suitable manner during the extrusion.
It is therefore also an object of the present invention to provide formulations comprising PVA as carrier for the active ingredient and at least an appropriate amount of an additive showing a melting point T lower than that of the PVA applied m And has a suitable viscosity such that the contained active ingredient remains stable during hot melt extrusion and can be extruded without any interruption.
In particular, the object of the present invention is therefore to provide compositions comprising PVA and additives and optionally further ingredients which allow the formulation of stable homogeneous mixtures in the form of solid dispersions containing active ingredients (API) and processing by hot-melt extrusion.
Summary of The Invention
Surprisingly, it has been found experimentally that the use of low molecular weight aminopolyols as plasticizers in polymer-containing compositions for Hot Melt Extrusion (HME) or melt extrusion processes has great advantages for the preparation of pharmaceutical formulations. Suitable aminopolyols are selected from D-glucosamine, D-galactosamine, mannosamine, D-fucosamine, N-acetyl-D-glucosamine, N-acetyllactosamine, N-acetylmannosamine, meglumine (D- (-) -N-methylglucamine) and sialic acid. A particularly suitable aminopolyol for this application is meglumine (D- (-) -N-methylglucamine). The use of these aminopolyols for producing pharmaceutical preparations comprising a polymer as carrier matrix is characterized in that the applied aminopolyols reduce the glass transition temperature T of the polymer-comprising composition in a hot-melt extrusion (HME) or melt extrusion process g And melting temperature T m . Advantageously, the applied aminopolyol additionally reduces the melt viscosity of the thermoplastic composition comprising the polymer.
An additional advantageous effect is the use of amino polyols, in particular meglumine, to stabilize thermally unstable Active Pharmaceutical Ingredients (APIs) and reduce their thermal degradation, and to act as a solubilizer for the applied poorly water-soluble APIs during hot-melt extrusion (HME) or melt extrusion, and to act as a stabilizer to prepare amorphous solid dispersions of APIs in a polymeric matrix during hot-melt extrusion (HME) or melt extrusion. This solubilization enhancement is particularly advantageous if an acidic API is used for the preparation of the composition according to the invention. Particularly preferred in this context is the use of aminopolyols in polyvinyl alcohol (PVA) -containing compositions for Hot Melt Extrusion (HME) or melt extrusion processes.
Furthermore, the use of these aminopolyols is particularly advantageous for the preparation of compositions in which
a) The aminopolyol is contained in a weight percentage content ranging from 5 to 40%,
b) comprises a polymer in a weight percentage content in the range of 60-95%, and
c) the API is included in a range of 0.01-40% by weight,
provided that the sum of all ingredients of the composition amounts to 100%.
Thus, part of the present invention is also a pulverulent composition comprising at least one thermoplastic polymer and, as plasticizer, at least one amino sugar, said amino sugar is selected from the group consisting of D-glucosamine, D-galactosamine, mannosamine, D-fucosamine, N-acetyl-D-glucosamine, N-acetyllactosamine, N-acetylmannosamine, meglumine (D- (-) -N-methylglucamine) and sialic acid, at least one active pharmaceutical ingredient, and optionally one or more additives selected from the group consisting of surfactants, antioxidants, stabilizers, solubility enhancers, pH control agents and flow control agents, said composition being obtained by:
a. the ingredients are physically blended or granulated into a homogeneous mixture,
b. hot melt extrusion or melt extrusion, and
c. and then formulated into a powder.
In particular, part of the invention is a powdered composition comprising polyvinyl alcohol as thermoplastic polymer in combination with meglumine as plasticizer and at least one active pharmaceutical ingredient. A particular advantage of the powdered composition is that it is a long-term stable amorphous solid dispersion of at least one active pharmaceutical ingredient and at least one amino sugar in a thermoplastic polymer carrier matrix.
The invention also provides a process for preparing the above-mentioned pulverulent composition according to the invention, characterized in that
a) Processing at least one thermoplastic polymer, at least one amino sugar, at least one active pharmaceutical ingredient, and optionally one or more additives selected from the group consisting of surfactants, antioxidants, stabilizers, dissolution enhancers, pH control agents, and flow control agents into a homogeneous mixture by physical blending or granulation, and
b) performing hot melt extrusion or melt extrusion of the homogeneous mixture, thereby constructing a solid dispersion of the API and the at least one amino sugar in a thermoplastic polymer carrier matrix, and
c) the extruded product was then formulated into a powder.
The method is characterized in that polyvinyl alcohol, meglumine and at least one active pharmaceutical ingredient and optionally one or more additives selected from the group consisting of surface-active substances, antioxidants, stabilizers, dissolution enhancers, pH control agents and flow control agents are processed into a homogeneous mixture by physical blending or granulation, and then the homogeneous mixture is processed by hot-melt extrusion or melt extrusion at a temperature of 150 ℃ or less and formulated into a powder.
Detailed Description
In the past few years, Hot Melt Extrusion (HME) has been introduced as a pharmaceutical manufacturing technology and is now a well-known processing method with the benefits of continuous efficient processes, limited number of processing steps, solvent-free, etc. In a hot melt extrusion process, a mixture of active ingredient(s) and thermoplastic excipients, as well as other functional processing aids, is heated and softened or melted in an extruder and extruded through a nozzle into various forms.
To prepare a particular hot-melt extruded dosage form, the active ingredient is embedded in a polymeric matrix. The requirements for a thermoplastic polymer intended for use as an HME excipient are as follows:
1. the polymer must be of a suitable pharmaceutical grade.
2. The glass transition temperature thereof must have a suitably low level.
3. The polymer must exhibit high thermal stability and it must have mechanical stability in terms of shear forces.
4. It must be non-toxic and must have high biocompatibility.
In this case, polyvinyl alcohol seems to be a suitable polymer. It is commercially available in various hydroxylation grades and in various pharmaceutical qualities.
In this regard, pharmaceutical grade polyvinyl alcohol appears to be a good choice for preparing formulations comprising active ingredients that are processed by HME.
PVA is a synthetic water-soluble polymer that has excellent film-forming, adhesive and emulsifying properties. It is prepared by polymerization of vinyl acetate and the functional acetate groups are partially or completely hydrolyzed to alcohol functional groups. The chemical and physical properties of PVA, such as viscosity, solubility, thermal properties, etc., depend on its degree of polymerization (chain length of the PVA polymer) and degree of hydrolysis. As the degree of hydrolysis increases, the solubility of the polymer in aqueous media increases, but the crystallinity and melting temperature of the polymer also increases. In addition, the glass transition temperature also varies depending on the degree of hydrolysis thereof. For example, 38% hydrolyzed materials have no melting point, but have a glass transition temperature of about 48 ℃, while 75% hydrolyzed materials have a melting temperature of about 178 ℃, 88% hydrolyzed materials have a melting point of about 196 ℃, and 99% materials have a melting point of about 220 ℃, but polymers tend to degrade rapidly above 200 ℃.
Polyvinyl alcohol is soluble in water, but is practically insoluble in almost all organic solvents, except in some cases, such as ethanol. This aspect makes the formation of amorphous and solid dispersions by spray drying very difficult.
However, polyvinyl alcohol (PVA) is known as a carrier in various routes of drug administration and is used for the treatment of various medical conditions, and it is widely used in various pharmaceutical dosage forms, including ophthalmic, transdermal, topical dosage forms, and in particular as a formulation for oral application.
The united states pharmacopeia-national formulary requires that acceptable polyvinyl alcohols for pharmaceutical dosage forms must have a percent hydrolysis of 85% to 89%, and a degree of polymerization of 500 to 5000. The degree of polymerization (DM) is calculated by the following formula:
DM ═ molar mass/((86) - (0.42 (degree of hydrolysis)))
The european pharmacopoeia requires that acceptable polyvinyl alcohols for pharmaceutical dosage forms must have an ester number of no more than 280 and an average relative molecular mass of 20,000 to 150,000. The percent hydrolysis (H) can be calculated from the formula:
H＝((100-(0.1535)(EV))/(100-(0.0749)(EV)))x100
where EV is the ester number of the polymer. Thus, according to the european pharmacopoeia monograph, only polymers with a hydrolysis percentage of more than 72.2% are acceptable.
As is well known for PVA, its high melting point is too high to be extruded with active ingredients having a lower melting point than the PVA grade applied.
This means that an agent must be found by means of which the melting point T can be lowered m . At the same time, it would be advantageous if the viscosity of the PVA-containing mixture was reduced by the same additives during extrusion.
By adding this additive to a mixture comprising PVA as a carrier for a pharmaceutically active ingredient, the aim is to obtain a formulation which forms a stable solid amorphous mixture with the active substance after treatment by hot melt extrusion.
In general, it is known that if a pharmaceutical formulation is difficult to compress into a tablet, a plasticizer, or a lubricant is added to improve the flowability of the pharmaceutical formulation. These additives are intimately mixed with all the compounds of the tablet formulation prior to tableting, so that a homogeneous mixture of the ingredients is obtained. Subsequently, the mixture is supplied for tableting, whereby the mixture is compressed under pressure to form tablets.
It has now surprisingly been found experimentally that the addition of at least further excipients to a blend with polyvinyl alcohol can lead to a significant reduction in the melting point of the blend. At the same time, the melts of these mixtures also exhibit a significantly reduced viscosity.
In particular, meglumine has excellent properties in this case. Meglumine or D- (-) -N-methylglucamine is an amino sugar derived from sorbitol, showing a pKa value of 9.60. It is a commonly used additive and an acceptable pharmaceutical excipient, approved by the FDA. It is used in contrast agents and can be applied by different routes of administration. As functional excipients, they are well known as stabilizers for active pharmaceutical ingredients and as solubilizers in pharmaceutical formulations. Meglumine is commercially available from Merck Millipore in high purity and pharmaceutical grade.
Meglumine is an amino sugar derived from sorbitol and can be used as a plasticizer. Meglumine and sorbitol exhibit similar physical properties such as low glass transition temperature and melting point, low melt viscosity, high thermal stability, good water solubility, etc.
Experiments conducted have shown that meglumine is not only suitable as an excipient for pharmaceutically active ingredients, but can also be used as a novel plasticizer or lubricant for use in formulations for melt extrusion.
Surprisingly, it has been found from experimental analytical data of PVA compositions comprising meglumine that meglumine is effective as a plasticizer and can be used to reduce the melting point and melt viscosity of mixtures comprising PVA as an excipient. It has also been found that by adding meglumine at lower temperatures, temperature sensitive pharmaceutically active ingredients can be extruded effectively and gently. Further, it was found through studies that meglumine has a stabilizing effect on the active pharmaceutical ingredient, and in particular, it has a stabilizing effect on an amorphous solid dispersion having a high drug concentration.
FIG. 1: structure of sorbitol
FIG. 2: structure of meglumine
In general, if a substance is intended for use in the preparation of a pharmaceutically active composition as described above, the substance should fulfill different basic requirements. It is known from the literature that poorly soluble active pharmaceutical ingredients can be formulated into compositions with suitable carriers and other additives via HME, thus providing improved bioavailability of the active ingredient.
Our experiments have now shown that compositions of poorly soluble active agents in combination with meglumine together with PVA as a carrier matrix can be processed by HME into amorphous solid dispersions with desirable beneficial properties.
The materials used to make hot melt extruded dosage forms must meet the same levels of purity and safety as the materials used in conventional dosage forms. Most of the compounds used to prepare hot melt extruded drugs have been used to prepare other solid dosage forms such as tablets, pills and transdermal agents.
The essential condition for the hot-melt extrudability of the polymer composition is a suitably low melting temperature T m Which is combined with the low melt viscosity of the mixture during the extrusion process. To lower the melting temperature, and generally also to lower the melt viscosity, plasticizers are needed to facilitate the hot melt extrusion process and to improve the physical and mechanical properties of the final product. Plasticizers can reduce the glass transition temperature T by increasing the free volume between polymer chains and their mobility g 。
Materials used to prepare pharmaceutical compositions by hot melt extrusion must have a degree of thermal stability in addition to acceptable physical and chemical stability. The thermal stability of all individual compounds is a prerequisite for the process and should be sufficient to withstand the preparation process. Not only must the polymer be stable at processing temperatures, but in particular the Active Pharmaceutical Ingredient (API) contained, especially heat sensitive or heat labile APIs, need to be protected from decomposition during hot melt extrusion. Here, in the present invention, the combination of PVA with meglumine as an additional carrier exerts a synergistic effect together with PVA during hot-melt extrusion, thereby stabilizing the active ingredient. This stabilization of the applied API is combined with lowering the melting point of the entire mixture.
Our experiments have now shown that compositions comprising polyvinyl alcohol as carrier matrix in combination with meglumine can be processed by hot melt extrusion at much lower temperatures than would be expected based on the melting temperature of the polymer involved. Advantageously, the extrusion can be carried out at a temperature of less than or equal to 150 ℃ and, under suitable conditions, the temperature in the extruder can be set even below 140 ℃.
As previously mentioned, hot melt extrusion can enhance drug solubility by stabilizing the drug in amorphous form in a polymer matrix and by deaggregating drug particles in an applied carrier. An additional effect of this manufacturing process by melt extrusion is improved wettability of the drug, and our own experimental results have shown that poorly water soluble drugs and hydrophilic polymers such as PVA can be processed into solid dispersions by HME. In this case, by the combination of PVA of the present invention with meglumine as an additional carrier, a significant improvement in bioavailability and solubility of the drug was found.
A prerequisite for a long-term stable formulation of the active ingredient is a solid amorphous dispersion in a carrier. The dosage forms obtained by melt extrusion generally have good long-term stability. However, the physical and chemical stability of the extruded product still depends on the nature of the API, the polymers included, excipients, additional ingredients and the physical state of the API in the final dosage form, as well as on storage and packaging conditions.
Advantageously, the positive impact of the inventive combination of PVA with meglumine and HME processing as additional carriers can also be seen herein.
The mixture of HME excipient including polymer (preferably PVA), plasticizer and ingredients should be fed into the feeder of the extruder, melted and extruded to build a stable amorphous solid dispersion with the API applied.
As used herein, the term "plasticizer" includes all compounds capable of plasticizing an applied polymer, preferably polyvinyl alcohol as described above. Plasticizers should be able to lower the glass transition temperature or softening point of the polymer in order to allow lower processing temperatures, extruder torques and pressures during the hot melt extrusion process. Plasticizers generally broaden the average molecular weight of a polymer, thereby lowering its glass transition temperature or softening point. Plasticizers also generally lower the viscosity of the polymer melt, allowing lower processing temperatures and extruder torques during hot melt extrusion. It is possible that the plasticizer will impart some particularly advantageous physical properties to the pharmaceutical formulation prepared.
As used herein, the term polyvinyl alcohol is intended to characterize grades of hot-melt extrudable or melt-extrudable polyvinyl alcohols and are those polymers having a viscosity ≦ 40mPa.s, where the viscosity is measured on a 4% aqueous solution at 20 ℃ (DIN 53015). These specific polyethylene-based grades that satisfy the conditions are preferably selected from: PVA 3-80, PVA 3-85, PVA 3-88, PVA 3-98, PVA4-88, PVA 4-98, PVA 5-74, PVA 5-82, PVA 6-88, PVA 6-98, PVA 8-88, PVA 10-98, PVAPVA 13-88, PVA 15-99, PVA 18-88, PVA 20-98, PVA23-88, PVA 26-80, PVA 26-88, PVA28-99, PVA 30-98, PVA 30-92, PVA 32-88, PVA 40-88, most preferably: PVA 3-88, PVA4-88, PVA 5-74, PVA 5-88, PVA 8-88 and PVA 18-88.
It was found experimentally that the inclusion of an aminopolyol as a plasticizer in the formulations of the present invention would alter the release profile thereof. Generally, increasing the amount of plasticizer present will increase the release rate of the therapeutic compound.
It is contemplated and within the scope of the present invention that an aminopolyol, preferably meglumine, may be used in combination with at least one other plasticizer in the formulations of the present invention.
The plasticizer used herein may be a solvent for the polymer, especially a solvent for the polyvinyl alcohol, at the temperature at which the formulation is prepared. Such plasticizers can dissolve polyvinyl alcohol when mixed with the polymer at temperatures above the characteristic temperature at which polyvinyl alcohol becomes soluble. Upon cooling, the mixture forms an amorphous dispersion of the active ingredient contained in the polymer matrix.
Plasticizers useful in the present invention include, for example, but are not limited to, low molecular weight amino alcohols.
Such plasticizers may be amino sugars selected from the group consisting of D-glucosamine, D-galactosamine, mannosamine, D-fucosamine, N-acetyl-D-glucosamine, N-acetyllactosamine, N-acetylmannosamine, meglumine (D- (-) -N-methylglucamine) and sialic acid. Preferably, meglumine (D- (-) -N-methylglucamine) acts as a plasticizer for the polyvinyl alcohol.
The amount of plasticizer used in the formulation will depend on its composition, physical properties, impact on the polymer, its interaction with other components of the formulation, the ability to solubilize the therapeutic compound, or other factors to be considered in preparing the pharmaceutical formulation. The amount of plasticizer present in the formulation affects its properties. For example, when the plasticizer is meglumine, it is typically present in an amount of no more than 30% by weight of the formulation.
Pharmaceutical preparation
As used herein, the term "active pharmaceutical ingredient" or "API" refers to an organic chemical substance that has a desired beneficial and therapeutic effect in a mammal. These compounds are generally classified as pharmaceuticals or biologicals. The structure of the therapeutic compound is not particularly critical so long as it can diffuse from the formulation when exposed to biological fluids.
APIs contemplated within the scope of the present invention include hydrophobic, hydrophilic and amphiphilic compounds. They may be in the form of their free acids, free bases or pharmaceutically acceptable salts. They may be derivatives or prodrugs of a given drug.
It is understood that certain APIs used in the present invention may contain asymmetrically substituted carbon atoms and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms from optically active starting materials, for example by resolution of the racemic form or by synthesis. Furthermore, it is recognized that cis and geometric trans isomers of therapeutic compounds are described and may be isolated as mixtures of isomers or as isolated isomeric forms. Unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended.
The API need not be soluble in any given formulation component. The API may be dissolved, partially dissolved or suspended in the polymer matrix of the formulation. The API must be stable under the hot melt extrusion process conditions used. By stable, it is meant that a substantial portion of the therapeutic compound will not significantly degrade or decompose throughout the hot melt extrusion process.
APIs that can be hot melt extruded in the formulations of the present invention can be used to treat indications such as, but not limited to, inflammation, gout, hypercholesterolemia, microbial infection, AIDS, tuberculosis, fungal infection, amoebic infection, parasitic infection, cancer, tumor, organ rejection, diabetes, heart failure, arthritis, asthma, pain, congestion, urinary tract infection, vaginal infection, epilepsy-related disorder, depression, psychosis, convulsions, diabetes, blood coagulation, hypertension, and birth control.
The API can be loaded into the final formulation according to the following technique. Typically, the therapeutic compound is loaded by pre-mixing the therapeutic compound with the polyvinyl alcohol and any other formulation components and hot melt extruding the mixture. When solids are present in the mixture, they may be, for example, but not limited to, powdered, crystalline, amorphous, granular, beaded, spherical, granular, and the like.
It will be appreciated that the amount of API loaded into the formulation may vary depending on, for example, the polymer to API or polymer to plasticizer to API ratio used in the pre-extruded polymer. While a given loading method may be optimal for a particular polyvinylalcohol-API combination, all of the described methods will generally result in some degree of API loading.
The therapeutic amount of API loaded into the formulation will vary depending on the pharmacological activity of the API, the indication being treated, the targeted dosing regimen, the intended method of administration, the integrity or stability of the final formulation, or other such reasons.
Hot melt extrusion process
As used herein, the term "hot melt extrudable" refers to a compound or formulation that can be hot melt extruded. Hot melt extrudable polymers are polymers that are sufficiently rigid at standard ambient temperatures and pressures but are capable of deforming or forming a semi-liquid state at high heat or pressure.
Although the above-mentioned method is referred to as hot melt extrusion, other equivalent methods may be used. By using any of these methods, the formulations can be shaped, for example, into tablets, pills, lozenges, suppositories, and the like as desired according to the desired mode of administration.
The hot melt extrusion process used in some embodiments of the invention is carried out at elevated temperatures, i.e., the heating zone(s) of the extruder is above room temperature (about 20 ℃). It is important to select an operating temperature range that minimizes degradation or decomposition of the active pharmaceutical compound during processing. The operating temperature range is typically in the range of about 60 ℃ to about 160 ℃ by the following experiments and the setting of the extruder heating zone(s). These experiments show that the operating temperature can be set at a temperature of 150 ℃ or less.
In a preferred embodiment of the invention, hot melt extrusion may be carried out using solid, powdered or other such feed materials comprising polyvinyl alcohol, meglumine and the active ingredient and optionally further compounds. Dry feed is advantageously used in the process of the present invention.
The hot melt extrusion process is generally described as follows. An effective amount of the powdered API is mixed with a suitable polymer that acts as a carrier matrix, and as disclosed herein, with a plasticizer such as meglumine. Other components may be added in various embodiments of the invention.
In the inventive embodiments of the present invention, it has proven advantageous when
a) The composition comprises aminopolyol in a weight percentage content ranging from 5 to 40%,
b) comprises a polymer in a weight percentage content in the range of 60-95%, and
c) the API is included in a range of 0.01-40% by weight,
provided that the sum of all ingredients of the composition amounts to 100%, depending on the desired release profile, the pharmacological activity and toxicity of the selected active pharmaceutical ingredient, and other such considerations. The mixture is then placed in an extruder feeder and passed through the heated zones of the extruder at a temperature that melts or softens the polymer and plasticizer to form a matrix in which the active ingredient is uniformly dispersed. The molten or softened mixture then exits through a die or other such element, at which point the mixture (now referred to as the extrudate) begins to harden. Because the extrudate is still warm or hot as it exits the die, it can be readily shaped, molded, chopped, milled, molded, spheronized into beads, cut into strands, tableted, or otherwise processed into a desired physical form. Preferably, the extrudate is formulated as a powdered composition.
The extruder used in the practice of the present invention can be any commercially available model equipped for handling dry feed and having a solids conveying zone, one or more heating zones, and an extrusion die. A two-stage single screw extruder is one such device. It is particularly advantageous if the extruder has a plurality of individual temperature-controllable heating zones.
Many conditions can be varied during the extrusion process to obtain particularly advantageous formulations. For example, these conditions include formulation composition, feed rate, operating temperature, extruder screw RPM, residence time, configuration, heating zone length, and extruder torque and/or pressure. Methods for optimizing these conditions are known to those skilled in the art.
Examples
Without any further explanation, it is believed that one skilled in the art can, using the preceding description, utilize the description to its fullest extent. Accordingly, the preferred embodiments and examples are to be considered as merely illustrative, and not restrictive of the disclosure in any way.
For a better understanding and explanation, the following examples are given within the scope of the present invention. These embodiments are also intended to illustrate possible variations.
The complete disclosures of all applications, patents, and publications mentioned above and below are incorporated herein by reference, and in the case of doubt, for illustration.
It goes without saying that in the examples given and in the rest of the description, the quoted percentage data of the components present in the composition always amount to a total of 100% and not more. The temperatures given are in units of ℃.
Method and material
1. Materials:
meglumine: 1-deoxy-1-methylamine sorbitol
Manufacturer: merck KGaA product
CAS number: 6284-40-8
EC number: 228-506-9
Mass: european pharmacopoeia, Japanese pharmacopoeia, United states pharmacopoeia
2. Experiments and methods
2.1 Experimental Equipment
Extruder:
Figure BDA0001857686540000151
mini blender KETSE 12/36D)
Physical blending of meglumine, other excipients and active ingredient:
Figure BDA0001857686540000152
vibration type mixer
Grinder to grind the extrudate into a powder:
Figure BDA0001857686540000153
20Universalmühle
·
Figure BDA0001857686540000154
granulating machine
3.1. Characterization method
3.1.1. Extrudability
First, use
Figure BDA0001857686540000155
The vibratory mixer homogeneously blends a mixture of meglumine, polymer and active ingredient (the concentration of polymer and active ingredient depends on their type and physical properties). The mixture is then loaded into an extruder having well-designed extrusion parameters such as feed rate, screw design, screw speed, extrusion temperature, etc. The settings of these parameters also depend on the type and physical properties of the polymer and the active ingredient. Since the boiling temperature of meglumine is typically 210 ℃, the extrusion temperature should be controlled below 210 ℃.
3.1.2. Milling of extrudates
The extrudate obtained can be micronized into fine particles using a mill (<1500 μm), or use
Figure BDA0001857686540000161
The granulator granulated the granules into beads (1500-.
3.1.3. Dissolution rate
For real-time dissolution performance, we used the following equipment:
the system 1:
sotax AT 7 online/offline
·Pumpe CY-7-50
Fraction collector: c61314, Kanal 3 Wege Ventilbalken fur
Figure BDA0001857686540000162
“
Agilent 8453 photometer
System 2
Sotax AT 7 online/offline
·Pumpe CP 7-35
Fraction collector: c61314, Kanal 3 Wege Ventilbalken fur vills "
Photometer Analytik Jena Specord 200 plus
Uniformity of API
The concentration of the active ingredient contained from different positions of the extrudate was analyzed by NMR spectroscopy.
4.1.2 results based on polyvinyl alcohol as thermoplastic Polymer for HME
4.1.2.1 Tg/Tm efficiency and melt viscosity reduction
Meglumine can act as a plasticizer for thermoplastic polymers and modify the behavior of hot melt extrusion. Although a minimum extrusion temperature of 190 ℃ to 200 ℃ (depending on the PVA type) is necessary to process the polymeric polyvinyl alcohol, only 140 ℃ to 150 ℃ is required to process the mixture with the addition of 25% meglumine.
FIG. 3: extrudates of polyvinyl alcohol and meglumine (75/25; left: extrudates processed at 140 ℃ C.; right: extrudates processed at 160 ℃ C.
Table 1: HME temperature of the mixture PVA/meglumine at different concentrations:
Figure BDA0001857686540000171
4.1.2.2. dissolution and solubility improvement of active ingredients
To evaluate the performance of meglumine as plasticizer and stabilizer for polymers and as solubility enhancer for acidic active ingredients, we selected model active ingredients with different pKa values:
1) ibuprofen: pKa (most acidic) ═ 3.8
2) Telmisartan: pKa (most acidic) of 3.65
3) Itraconazole: pKa (most basic) of 3.92
4) Naproxen: pKa (most basic) 4.19
Extrudates from API and polyvinyl alcohol were analyzed for dissolution, polymorphism and stability with and without meglumine.
Example 1: ibuprofen (Tm 78 deg.C, acid active ingredient)
A: an extrusion process: extrusion of ibuprofen (20-30%) and PVA4-88 (70-80%) was not feasible because the ibuprofen Tm for PVA4-88 was too low (78 ℃ (Tm 190 ℃). In this case, it is necessary to add a plasticizer to lower the Tg/Tm of the PVA and to make the extrusion process feasible. We added 25% meglumine as a plasticizer and the mixture with meglumine was extrudable:
FIG. 4: extrudate of 20% ibuprofen with PVA/meglumine (75/25): 80 ℃/150 ℃/150 ℃/150 DEG C
B: polymorphic form of extruded ibuprofen:
the polymorphic form of the extruded ibuprofen was evaluated and the extrudate contained ibuprofen in amorphous form at a concentration of 20% to 40%:
FIG. 5: DSC of an extruded composition comprising amorphous ibuprofen in a concentration of 20% w/w.
FIG. 6: DSC of an extruded composition comprising amorphous ibuprofen in a concentration of 30% w/w.
FIG. 7: DSC of an extruded composition comprising amorphous ibuprofen at a concentration of 40% w/w.
C: distribution of 20% w/w ibuprofen loaded in SGFsp medium at 37 ℃:
FIG. 8: dissolution of 20% w/w ibuprofen loaded in SGFsp medium at 37 ℃.
Example 2: itraconazole
A: extrusion process
Preparation of a physical mixture of PVA 4-88/itraconazole (70/30) required an extrusion temperature of 210 ℃. With the addition of 17.5% meglumine as plasticizer, the extrusion temperature was reduced to 180 ℃.
B: dissolution of itraconazole in SGFsp medium at 37 ℃:
the dissolution rates of itraconazole and meglumine are the same as those of itraconazole without meglumine. However, with the addition of meglumine, the processing temperature can be very effectively lowered.
FIG. 9: dissolution of 30% w/w itraconazole loaded in SGFsp Medium at 37 ℃
Example 3: telmisartan
A: an extrusion process: the physical blend of PVA 4-88/telmisartan (85/15) required an extrusion temperature of 240 ℃ because telmisartan had a high Tm of 261-. In the case of 21.25% meglumine added to the mixture as a plasticizer, the extrusion temperature can be lowered from 240 ℃ to 180 ℃.
B: polymorphic forms of extruded telmisartan: DSC data showed that the extrudate of 15% telmisartan within neat PVA4-88 was semi-crystalline, whereas the extrudate of PVA/meglumine/telmisartan (63.75/21.25/15) was completely amorphous:
FIG. 10: DSC showed that the extrudate from PVA/telmisartan was semi-crystalline
FIG. 11: DSC showed that the extrudate from PVA/meglumine/telmisartan is 100% amorphous
C: dissolution rate of telmisartan at 37 ℃ in phosphate buffer pH 7.2 medium:
the dissolution rate of telmisartan can be effectively improved by adding 21.25% of meglumine, which is 5.6 times higher than the dissolution rate of telmisartan without adding meglumine. Thus, in the case of telmisartan, meglumine is not only a plasticizer, but it is also an effective solubility enhancer, which improves the water solubility of BCS class II and class IV active ingredients.
FIG. 12: dissolution of Telmisartan (15% w/w loading) in phosphate buffer pH 7.2 Medium at 37 ℃
Example 4: naproxen
A: an extrusion process: the physical blend of PVA 4-88/naproxen (70/30) required an extrusion temperature of 200 ℃ because of the T of naproxen m The temperature was 152 ℃. In the case of 21.25% meglumine added to the mixture as a plasticizer, the extrusion temperature can be lowered from 200 ℃ to 160 ℃.
B: dissolution of naproxen in phosphate buffer pH 7.4 medium at 37 ℃:
the dissolution rate of naproxen can be effectively improved by adding 21.25% of meglumine, which is 1.26 times higher than the dissolution rate of the naproxen without adding the meglumine. Thus, in the case of naproxen, meglumine is not only a plasticizer, but it is also an effective solubility enhancer, which improves the water solubility of BCS class II and class IV active ingredients.
FIG. 13: dissolution of naproxen (30% w/w loading) in phosphate buffer pH 7.4 medium at 37 ℃
4.1.2.3. Homogeneity of active ingredients within extruded products
Table 2: the concentration of ibuprofen detected in the extrudate (PVA/meglumine/ibuprofen 60/20/20) should contain 20% ibuprofen:
Figure BDA0001857686540000191
Figure BDA0001857686540000201
table 3: the concentration of itraconazole detected in the extrudate (PVA/meglumine/itraconazole 52.5/17.5/30) should contain 30% itraconazole:
Figure BDA0001857686540000202
4.1.2.4. improved thermal stability of active ingredients
Ibuprofen cannot be extruded with PVA alone because of the T of PVA g Too high for ibuprofen. In this case, a plasticizer is required. Experiments have shown that ibuprofen can be extruded at 150 ℃ if meglumine is added as plasticizer. Literature data show that if the composition is processed by HME, 11.6% of the contained ibuprofen degrades at 144 ℃. In contrast, no degradation of ibuprofen was observed in the presence of meglumine (in the case of ibuprofen as active ingredient, 99% of ibuprofen was detected in the final extrudate). This means that it was found experimentally that in the case of ibuprofen, meglumine not only acts as a plasticizer, but is also effective for stabilizing against the negative effects of high temperatures. Thus, meglumine is used as a stabilizer in these compositions in the presence of ibuprofen.
Table 4: ibuprofen detected in extrudates containing meglumine:
Figure BDA0001857686540000203
Figure BDA0001857686540000211
table 5: ibuprofen detected in the extrudate without meglumine (sorbitol as plasticizer):
Figure BDA0001857686540000212
4.1.2.5 summary of results
Experiments clearly show that meglumine can be used excellently as plasticizer in pharmaceutical compositions containing PVA as carrier and processed by HME. In particular, these compositions exhibit the following advantageous characteristics:
effective reduction of processing temperature during HME (samples with all 3 APIs)
Protection of the thermosensitive API from thermal degradation (sample with ibuprofen)
Improved water solubility of the acidic active ingredient (samples with ibuprofen and telmisartan)
Unexpected chemical interaction with active principle (samples with all 3 APIs)

Claims (8)

1. Use of a low molecular weight aminopolyol as a plasticizer in a composition comprising polyvinyl alcohol for the preparation of a pharmaceutical formulation in the form of an amorphous solid dispersion of an active pharmaceutical ingredient and processed by a Hot Melt Extrusion (HME) or melt extrusion process,
wherein the amino polyol is meglumine, and wherein the meglumine lowers the glass transition temperature, T, of a composition comprising polyvinyl alcohol in a Hot Melt Extrusion (HME) or melt extrusion process g And melting temperature T m ，
Wherein
a) The weight percentage content of the contained meglumine is 5-40%,
b) containing 60-95% by weight of polyvinyl alcohol, and
c) comprises 0.01-40% by weight of API,
provided that the sum of all ingredients of the composition amounts to 100%.
2. Use according to claim 1, characterized in that the aminopolyol reduces the melt viscosity of the thermoplastic composition comprising polyvinyl alcohol.
3. Use according to claim 1 or 2, characterized in that the aminopolyol stabilizes the thermally labile Active Pharmaceutical Ingredient (API) and reduces its thermal degradation.
4. Use according to claim 1 or 2, characterized in that the aminopolyol acts as a stabilizer of the amorphous solid dispersion of the API for preparation in the polyvinyl alcohol carrier matrix.
5. A powdered composition comprising at least one polyvinyl alcohol, and meglumine as plasticizer, at least one active pharmaceutical ingredient and optionally one or more additives selected from the group consisting of surface-active substances, antioxidants, stabilizers, dissolution enhancers, pH control agents and flow-regulating agents, said composition being obtained by:
A. the ingredients are physically blended or granulated into a homogeneous mixture,
B. hot melt extrusion or melt extrusion, and
C. then preparing into powder; and is
a) The weight percentage content of the contained meglumine is 5-40%,
b) containing 60-95% by weight of polyvinyl alcohol, and
c) comprises 0.01-40% by weight of API,
provided that the sum of all ingredients of the composition amounts to 100%.
6. The powdered composition of claim 5 which is a long-term stable amorphous solid dispersion of at least one active pharmaceutical ingredient and meglumine in a polyvinyl alcohol carrier matrix.
7. Process for preparing the pulverulent composition according to claim 5 or 6, characterized in that
A) Processing at least one polyvinyl alcohol, meglumine, at least one active pharmaceutical ingredient, and optionally one or more additives selected from the group consisting of surface-active substances, antioxidants, stabilizers, dissolution enhancers, pH control agents, and flow control agents into a homogeneous mixture by physical blending or granulation, wherein
a) The weight percentage content of the contained meglumine is 5-40%,
b) containing 60-95% by weight of polyvinyl alcohol, and
c) comprises 0.01-40% by weight of API,
provided that the sum of all ingredients of the composition amounts to 100%;
B) processing the homogeneous mixture by hot melt extrusion or melt extrusion, thereby constructing an amorphous solid dispersion of API and meglumine in a polyvinyl alcohol carrier matrix; and
C) and then formulated into a powder.
8. The process according to claim 7, characterized in that polyvinyl alcohol, meglumine and at least one active pharmaceutical ingredient and optionally one or more additives selected from the group consisting of surface-active substances, antioxidants, stabilizers, solubility enhancers, pH control agents and flow control agents are processed into a homogeneous mixture by physical blending or granulation, and then the homogeneous mixture is processed by hot melt extrusion or melt extrusion at a temperature of 150 ℃ or less and formulated into a powder.
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